The current standard of care for the treatment of chronic HCV is alfa interferon, injected subcutaneously (under the skin) three times a week, combined with oral ribavirin capsules taken twice a day. Course of treatment is six months to a year. Alfa interferon is a naturally occurring protein produced by the body to interfere with a virus' ability to infect cells. Bio-engineered alfa interferon is used to treat many cancers and was investigated in the 1980s as a possible HIV treatment, although without success. In HCV, the success rate of alfa interferon monotherapy is only 5 to 25%. Success is defined as achieving an undetectable HCV viral load (<100 copies per ml) six months after finishing treatment (sustained response). In June of 1998, the FDA approved Schering-Plough's Rebetron, a kit containing two products packaged together -- Intron A, the company's brand of alfa interferon, and ribavirin capsules. Interferon/ribavirin combination therapy achieves an overall sustained response rate of 41%, clearly superior to interferon monotherapy.
Many people can't tolerate interferon's side effects. These can include everything from what are generously called "flu-like" symptoms to weight loss, low white blood cells and platelets, irritability, depression, and, sometimes, suicidal thoughts. The side effects are usually worse during the first weeks of treatment, and each person experiences them differently. Ribavirin can cause severe anemia (low red blood cells), and both drugs can cause severe birth defects.
While everyone looks forward to the day when interferon treatment is obsolete, the next step toward more successful and tolerable HCV treatment is pegylated interferon. Pegylation is a process that allows interferon to stay in your body at consistent levels for up to a week. Currently available interferons only stay in your body for about a day, resulting in insufficient pressure on the virus in between the usual three weekly doses. By providing steady levels of drug, pegylated interferon allows for more convenient, once weekly dosing, as well as higher success rates. Preliminary results of Phase III trials of two pegylated interferons in development are promising. The data were presented at the 35th Annual Meeting of the European Association for the Study of Liver Disease (EASL) in May. Neither trial included co-infected participants, but early data from ongoing co-infection trials, as well as the experience of physicians who treat co-infected patients, suggest that the response rates of co-infected individuals are similar to those of people with only HCV.
PEG-Intron (pegylated interferon alfa-2b)
One study compared three doses of Schering-Plough's PEG-Intron (0.5, 1.0 or 1.5 micrograms per kilogram [ug/kg], once a week) and standard dosing of Intron A (three million international units, three times a week). The trial lasted 72 weeks -- 48 weeks on treatment, with 24 weeks of follow-up. The 1,219 participants had never undergone interferon treatment for HCV. The majority were Caucasian (91%) and male (63%), with HCV viral loads above two million copies per ml (73%) and genotype 1 (70%), the most predominant genetic strain of HCV and the hardest to treat. Nine percent of the participants had fibrosis scores of 3 or 4 (cirrhosis).
All three doses of PEG-Intron had significantly higher sustained response rates (undetectable viral load six months after completing treatment) than Intron A (only 12%). The most successful overall rate (25%) was seen in participants who received PEG-Intron at the 1.0 ug/kg dose. People with HCV viral loads under two million to begin with and genotypes 2 or 3 usually respond best to interferon treatment. As expected, this proved to be the case in this trial. The highest sustained response rate (62%) was seen in participants with beginning HCV viral loads under two million and genotypes 2 or 3 on the 1.5 ug/kg dose. This compares to only an 8% sustained response rate in participants with beginning HCV viral loads over two million and genotype 1 on the 1.0 ug/kg dose.
Pegasys (pegylated interferon alfa-2a)
The other pegylated interferon in development is Hoffmann-La Roche's Pegasys. Roche's study included 531 interferon-naïve participants. Half of the participants received Pegasys (180 micrograms once a week). The other half received Roferon, Roche's brand of alfa interferon. Participants in the Roferon arm received six million international units (MIU) three times a week for the first twelve weeks, followed by standard three MIU three times a week for the remaining 36 weeks of treatment. Although some HCV physicians begin interferon treatment at these higher doses, hoping to achieve better results, the decision to use this approach in a head-to-head comparison trial is surprising.
The study group was similar to that of the PEG-Intron trial -- predominantly Caucasian (85%), male (67%), and genotype 1 (61%). The percentage of participants with HCV viral loads above two million copies wasn't reported, but the average viral load was over 7.5 million. Thirteen percent of the participants had or were developing cirrhosis.
The overall sustained response rate in the Pegasys arm at 72 weeks was 39%, compared to 19% in the Roferon arm. Looking at the results by genotype, the sustained response rates for participants in the Pegasys arm were 28% for genotype 1, 64% for genotype 2, and 54% for genotype 3. These compare to 7%, 50% and 32% respectively in the Roferon arm. Baseline HCV viral load was also an important factor in the success of treatment. Participants who began Pegasys with viral loads under two million achieved a sustained response rate of 52% compared to 27% for those who began with viral loads over two million. The respective rates in the Roferon arm were 25% and 13%.
Although many people had hoped otherwise, the side effects of pegylated interferon are no less severe than those of standard interferon. In the first study, dropout rates due to side effects in the PEG-Intron arms were 9-11%. This compares to 6% in the Intron A arm. Similar percentages of participants required dose reductions due to side effects: 9-15% in the PEG-Intron arms and 6% in the Intron A arm. In the second study, the dropout rates due to side effects were 7% in the Pegasys arm and 10% in the Roferon arm. Dose reductions due to side effects were necessary for 9% in the Pegasys arm and 14% in the Roferon arm.
It's tempting to compare the two pegylated interferons based on the results of these Phase III trials. Pegasys' overall sustained response rate of 39% would seem to make it superior to PEG-Intron's best overall rate of 25% at the 1.0 ug/kg dose. And looking only at sustained response rates for people with genotype 1, Pegasys achieved 28%, while PEG-Intron achieved only 14% (at the 1.0 and 1.5 ug/kg doses). However, the data in these studies were broken down and presented differently, and the PEG-Intron trial included more than twice as many participants. Direct comparisons need to be made carefully. Men don't usually respond as well as women to interferon treatment, and people of African descent don't usually respond as well as other ethnic groups. If the data from these trials were available based on sex and race, the variations in response rates might be even more extreme.
Undetectable HCV viral load six months after completing treatment is the measure of success in these trials, but a primary goal of treatment for HCV is histologic improvement -- in other words, a healthier liver. This is measured by normalized liver enzymes, lower or undetectable viral load, and a follow-up liver biopsy. Even without sustained response or significantly lower viral load, treatment can give your liver a much-needed break. Histologic improvement at week 72 was seen in 63% of the participants on Pegasys and 55% of those on Roferon. Similar information on PEG-Intron and Intron A wasn't presented.
Pegylated interferon + ribavirin
The additional benefits of combining pegylated interferon with ribavirin have been highly anticipated. Results from two small Phase II trials of combination therapy were presented in May. One looked at PEG-Intron +/- ribavirin in 72 people; the other looked at Pegasys + ribavirin in 20 people. As hoped, combination therapy achieved higher overall sustained response rates than either pegylated interferon monotherapy or alfa interferon + ribavirin, the current standard of care. The highly preliminary results must be viewed cautiously because of the small number of participants. No co-infected individuals were included in either trial.
Both PEG-Intron and Pegasys are likely to receive FDA approval late this year or early in 2001. Meanwhile, a large program is planned that will allow people with chronic HCV free access to Pegasys. Three-quarters of the program participants will also receive ribavirin. Because there is so little data on pegylated interferon in combination with ribavirin, the FDA is calling this a safety trial rather than a conventional expanded access program. It is expected to begin this summer. Unfortunately, co-infected individuals are excluded from the program.